Methotrexate

Methotrexate is used in the treatment of severe psoriasis [1–3]. It is an antifolate and anti‐metabolite drug that blocks dihydrofolic acid reductase, inhibiting purine and pyrimidines synthesis, and depleting intracellular stores of folate reducing synthesis of DNA and RNA causing cellular arrest. Moreover, there are increased levels of intracellular adenosine secondary to 5‐aminoimidazole‐4‐carboxamide ribonucleotide formyltransferase inhibition. Adenosine stimulates hepatic stellate cells (liver‐specific mesenchymal cells) to release pathological collagen fibers promoting liver fibrosis. Methotrexate has also been shown to promote proliferation of hepatic stellate cells.

The resultant liver damage can range from mild hepatitis to, very rarely, fulminant hepatic failure. Elevation in serum aminotransferase is common. High‐dose methotrexate can increase alanine amino transferase (ALT) to 10–20 times the upper limit of normal (ULN). These levels often improve within 12–48 hours of treatment. Moderate methotrexate doses can cause elevation in serum aminotransferase in 15–50% of the population, but this is often mild and self‐limiting. The fluctuation seen in LFTs could also be dependent on timings of blood tests taken before or after the dose of methotrexate. Studies have demonstrated that concurrent folic acid replacement reduces the rate of ALT elevation in patients on low‐dose methotrexate. Acute jaundice or liver failure secondary to drug induce liver injury with methotrexate is very rare. With high rates of coexistent fatty liver, low level changes in serum liver tests are very commonly encountered coincidentally.

Hepatitis B can be reactivated by low‐dose methotrexate, even in those with normal ALT, no detectable hepatitis B virus (HBV) DNA and no hepatitis B e antigen. This acute reactivation can result in hepatic failure, liver transplantation, and death. It is therefore important to complete a viral hepatology screen prior to methotrexate therapy. Patients with detectable HBsAg should be reviewed by a gastroenterologist/hepatologist, and are usually treated with antivirals when immunosuppressed. Patients with prior exposure to hepatitis B (cAb positive, sAg negative) are usually monitored every three months.

Liver fibrosis is the result of deposition of pathologic collagen‐rich extracellular matrix, in response to continuing chronic liver injury. End‐stage liver disease or cirrhosis causes portal hypertension, resulting in varices, ascites, and encephalopathy, for which the only curative therapy is liver transplantation. The risk of methotrexate‐induced liver fibrosis is heightened by the presence of obesity, diabetes, increased age, and intake of more than 10 units of alcohol per week. With such a high prevalence of fatty liver, methotrexate is not usually the culprit.

Around 30% of patients treated with methotrexate will develop mild to moderate histological changes, including fatty deposition and mild inflammation. Up to 15% of patients treated with methotrexate will develop mild fibrosis and 1% will have moderate fibrosis or cirrhosis often within 2–10 years of commencing therapy. Some patients will develop portal hypertension without significant fibrosis, suggesting that methotrexate could result in nodular regeneration of the liver. Hepatocellular carcinoma in patients treated with methotrexate is rare and the evidence is limited to case reports.

Liver biopsy has been considered the gold standard to diagnose liver fibrosis. Previously, patients would undergo biopsy after 1, 4, and 8 g of cumulative methotrexate. However, diagnostic accuracy is impeded by sampling error and inter‐pathologist variation in interpretation. Moreover, liver biopsy is invasive and associated with morbidity including pain, bleeding, infection, and damage to nearby organs.

In modern hepatic clinical practice fibrosis scores and measurement of transient elastography (TE) using a FibroScan® (Echosens) have become well established for diagnosing liver fibrosis without biopsy. Box 13.1 shows our recommendations for their use in patients on methotrexate.

Retinoids

Retinoids are used in the management of acne, psoriasis, and Darier’s disease. A rise in serum aminotransferases is seen in around 20% of patients but its significance is uncertain. Retinoids can cause acute hepatitis but rarely cause chronic liver disease. Monitoring for retinoids [5] consists of monitoring LFTs at the start of therapy. If they are persistently abnormal, reduce and potentially stop treatment.

Azathioprine

Azathioprine is used to treat various dermatological conditions including pemphigus, pemphigoid, eczema, systemic lupus erythematosus, and dermatomyositis. Elevation of liver enzymes and cholestasis are not uncommon, but are usually reversible on withdrawal of azathioprine. A hypersensitivity reaction to azathioprine is rare, but can result in cholestatic jaundice, portal fibrosis, nodular regenerative hyperplasia, hepatocellular necrosis, fever, and shock. LFTs should be monitored every three months.